The progressive forms of leishmaniasis are the result of the multiplication of Leishmania in the primary cutaneous lesion, and its dissemination to distant visceral and/or cutaneous sites. However, the pattern of development of disease is determined not only by the immune competence of the host, but also by the physiological properties of the parasite. The objective of the studies outlined in this proposal is to understand those host and parasite factors responsible for the development of disseminated disease. Leishmania major and Leishmania mexicana infections in inbred strains of mice will be examined. The first series of studies will document the dissemination of the parasite in two strains of athymic, nude mice to determine whether non-immunological host factors modulate the pattern of development of systemic disease. With the use of a technique developed in this laboratory to enumberate viable parasites in tissue, the dissemination of Leishmania from the site of inoculation (footpad) to the liver, spleen, and distant cutaneous sites will be followed. An analysis of the role for mononuclear phagocytes, and granulocytes, in the dissemination process will be performed, with particular emphasis on the capacity of parasitized, host cells to initiate foci of infection in extravascular sites. The strengths and limitations of cell-mediated immunity in preventing the dissemination of Leishmania and restricting its growth in metastatic sites will be examined by adoptive immunization experiments. The role of helper T cells will be addressed.